Skip to main content

BRIEF RESEARCH REPORT article

Front. Pharmacol.
Sec. Pharmacogenetics and Pharmacogenomics
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1516375

Clinical implications of a gain of function genetic polymorphism in DPYD (rs4294451) in colorectal cancer patients treated with fluoropyrimidines

Provisionally accepted
Elena De Mattia Elena De Mattia 1Jerry Polesel Jerry Polesel 2Lucia Scarabel Lucia Scarabel 1Erika Cecchin Erika Cecchin 1*
  • 1 Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS,, Aviano (PN), Italy
  • 2 Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS,, Aviano (PN), Italy

The final, formatted version of the article will be published soon.

    Dihydropyrimidine dehydrogenase (DPD, DPYD) is the rate-limi ng enzyme for the detoxifica on of fluoropyrimidines (FLs). The rs4294451 is a regulatory DPYD polymorphism that has recently been func onally characterized and associated with increased DPD expression in the liver. The aim of the present study was to test the clinical implica ons of being a carrier of rs4294451 in a cohort of 645 FL-treated colorectal cancer pa ents. Carriers of at least one DPYD rs4294451-T variant allele had a lower risk of developing NCI-CTC grade 4-5 hematological (OR=0.39, 95%CI: 0.15-0.98, addi ve model) and hematological/non-hematological (OR=0.44, 95%CI: 0.22-0.88, dominant model) FL-related toxicity. Pa ents with the DPYD rs4294451-T allele also had a longer me to severe toxicity development a er FL treatment start (hematological, HR=0.27, 95%CI: 0.09-0.79, Fine-Gray test= 0.1569; hematological/non-hematological: HR=0.38, 95%CI: 0.17-0.85, Fine-Gray test= 0.0444). It is worth no ng that while being at lower risk of toxicity, DPYD rs4294451-T allele carriers tend also to present a shorter overall survival (HR=1.41, 95%CI:1.05-1.90, log-rank p=0.0406). These findings demonstrate a clinical effect of DPYD-rs4294451 polymorphism coherent with the recently described func onal effect. Further inves ga on is warranted to elucidate the poten al clinical value to the rs4294451 polymorphism as a toxicity and especially as an efficacy marker in colorectal cancer.

    Keywords: DPYD, rs4294451, FLUOROPYRIMIDINE, Toxicity, colorectal cancer

    Received: 24 Oct 2024; Accepted: 22 Nov 2024.

    Copyright: © 2024 De Mattia, Polesel, Scarabel and Cecchin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Erika Cecchin, Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS,, Aviano (PN), Italy

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.